16-70252728-T-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001605.3(AARS1):c.2900A>T(p.Lys967Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,614,088 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0094 ( 10 hom., cov: 33)

Exomes 𝑓: 0.012 ( 147 hom. )

Consequence

AARS1
NM_001605.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

AARS1 (HGNC:20): (alanyl-tRNA synthetase 1) The human alanyl-tRNA synthetase (AARS) belongs to a family of tRNA synthases, of the class II enzymes. Class II tRNA synthases evolved early in evolution and are highly conserved. This is reflected by the fact that 498 of the 968-residue polypeptide human AARS shares 41% identity witht the E.coli protein. tRNA synthases are the enzymes that interpret the RNA code and attach specific aminoacids to the tRNAs that contain the cognate trinucleotide anticodons. They consist of a catalytic domain which interacts with the amino acid acceptor-T psi C helix of the tRNA, and a second domain which interacts with the rest of the tRNA structure. [provided by RefSeq, Jul 2008]

AARS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0089383125).

BP6

Variant 16-70252728-T-A is Benign according to our data. Variant chr16-70252728-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 220723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-70252728-T-A is described in Lovd as [Benign]. Variant chr16-70252728-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00941 (1433/152320) while in subpopulation NFE AF= 0.0139 (945/68032). AF 95% confidence interval is 0.0132. There are 10 homozygotes in gnomad4. There are 700 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARS1	NM_001605.3 link	c.2900A>T	p.Lys967Met	missense_variant	Exon 21 of 21	ENST00000261772.13	NP_001596.2	P49588-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AARS1	ENST00000261772.13 link	c.2900A>T	p.Lys967Met	missense_variant	Exon 21 of 21	1	NM_001605.3	ENSP00000261772.8		P49588-1

Frequencies

GnomAD3 genomes

AF:

0.00942

AC:

1433

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0111

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00762

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0139

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00992

AC:

2493

AN:

251344

Hom.:

AF XY:

0.00994

AC XY:

1351

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00302

Gnomad AMR exome

AF:

0.00798

Gnomad ASJ exome

AF:

0.0255

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.00853

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.0139

GnomAD4 exome

AF:

0.0123

AC:

17971

AN:

1461768

Hom.:

147

Cov.:

AF XY:

0.0120

AC XY:

8758

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00230

Gnomad4 AMR exome

AF:

0.00847

Gnomad4 ASJ exome

AF:

0.0290

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00182

Gnomad4 FIN exome

AF:

0.00806

Gnomad4 NFE exome

AF:

0.0139

Gnomad4 OTH exome

AF:

0.0117

GnomAD4 genome

AF:

0.00941

AC:

1433

AN:

152320

Hom.:

Cov.:

AF XY:

0.00940

AC XY:

700

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00241

Gnomad4 AMR

AF:

0.0110

Gnomad4 ASJ

AF:

0.0280

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00762

Gnomad4 NFE

AF:

0.0139

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0144

Hom.:

Bravo

AF:

0.00949

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.00959

AC:

1164

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0150

EpiControl

AF:

0.0142

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AARS1: BS1, BS2 -

Sep 03, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Charcot-Marie-Tooth disease axonal type 2N

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2N;C4225361:Developmental and epileptic encephalopathy, 29;C5562044:Leukoencephalopathy, hereditary diffuse, with spheroids 2;C5562057:Trichothiodystrophy 8, nonphotosensitive

Benign:1

Aug 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.46

REVEL

Benign

0.23

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

0.99

Vest4

0.39

MVP

0.68

MPC

0.78

ClinPred

0.028

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.13

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over